REGULATION OF GROWTH AND REPRODUCTION

Child Health And Human Development

Investigators

Linked publications, trials & patents

Abstract

Based on its high level expression in the developing brain and on the finding of mental retardation in cases of human insulin-like growth factor 1 (IGF1) gene deletions, IGF1 is thought to play an important role in brain development. We have shown that the IGF1 gene deleted mouse brain demonstrates a generalized reduction in neuronal size and in volume of nerve processes? suggesting compromised circuitry. We have also shown that glucose utilization in the developing and injured brain is highly correlated with IGF1 and IGF1 receptor expression, and that IGF1 null mouse model demonstrates a profound reduction in brain glucose utilization. We have recently found that specific signaling mechanisms involved in peripheral insulin-mediated glucose transport and glycogen synthesis are impaired in the IGF1 null brain. The serine/threonine kinase Akt is hypo-phosphorylated in IGF1 null neurons, and is associated with reduced levels and altered subcellular localization of the insulin-sensitive glucose transporter in these same neurons. Akt-induced serine phosphorylation of glycogen synthase kinase 3b (GSK3b) is also reduced and is associated with reduced glycogen stores in IGF1 null neurons. GSK3b is thought to be involved in tau phosphorylation, and we found hyperphosphorylation of this microtuble-associated protein in the IGF1 null brain. These data suggest that IGF1 serves an anabolic, insulin-like role in brain development, promoting neuronal process growth and synaptogenesis, and suggest also that IGF1 deficiency may lead to some of the alterations in brain homeostasis typical of Alzheimer disease, such as decreased glucose metabolism and tau hyperphosphorylation. Extending this line of investigation to the non-human primate brain, which has special relevance to the human, we found that estrogen, which reputedly prevents or ameliorates Alzheimer disease, augments IGF1 in the rhesus monkey frontal cortex. Thus, estrogen's saluatry effects on brain function and neuronal survival by be mediated by locally produced IGF1. Current studies are investigating other mechanisms to enhance brain IGF1 expression, with the goal of preventing or treating mental retardation or dementias of many different causes.